17alpha-butadiynyl-17beta-hydroxy derivatives of perhydrocyclopentenophenanthrene and process for preparation of same



United States Patent 7" 3,164,617 17oc-BUTADIYNYL- 7fl-HYDROXY DERIVA- TIVES OF PERHYDROCYCLOPENTENO- PHENANTHRENE AND PROCESS FOR PREPARATION OF SAME Peter Feather and Vladimir Petrow, London, England, assignors to The British Drug Houses Limited N0 Drawing. Filed Jan. 29,1963, Ser. No. 254,606 Claims priority, application Great Britain Feb. 2, 1962 28 Claims. (Cl; 260397.4) .1

organic compounds and has particular reference to a new class of steroidal materials, namely the 17a-butadiynyl- 17/3-hydroxy derivatives of perhydrocyclopentenophenanthrene and to 'a process of their preparation.

The new compounds of the present invention have valuable biological properties in that, in general, they have claudogenic properties (see. Petrow, J. Pharm. PharmacoL, 1960, 12, 1704), or they may be readily converted into compounds having valuable biological properties. Thus, for example, they undergo catalytic hydrogenation to l7u-butyl-17fi-hydroXy derivatives. They can have hormal properties including oestrogenic, progestational and ovulation inhibiting properties.

Thus 17a-butadiynyloestradiol 3-methy1 ether has oestrogenic and claudogenic properties.- Such compounds as 17oc-butadiyny1androst-5-en-3e, l7 3-diol and '17a-butadiynyl-6-methylandrost-Sen-35,17,8-diol have claudogenic properties and in particular anti-nidation properties without concomitant significant oestrogenic activity.

Other valuable 17a-butadiynyl-l7p-hydroxy derivatives with claudogenic properties include derivatives of Compounds having such properties are valuable in the veterinary field particularly for application to the dog and cat species. Thus unwantedlitters in, for example, sheep dogs and pedigree animals and sometimes in domestic pets can be disadvantageous. By administration of one of the claudogenic compounds of the present invention the appearance of such unwanted litters maybe prevented. Similarly in cats the administration of c1audo-,

genic compounds is often of value. Not only does such administration prevent the appearance of unwanted litters,

but it eliminates the need for castration so that normal reproduction can take place if subsequently desired.

The claudogenic compounds of the present'invention are of value for the control of infestation by domesticallyencountered rodents. especially rats and mice. For example, the 3-methyl derivative of 17a-butadiynyl oestradiol may be administered for this purpose in a'suitable'bait. An advantage of the claudogenic compounds ofjthe present invention over the hitherto available rat and mouse poisons is the virtual absence of toxicity to domestic animals if the treated bait is accidentally consumed. This form of claudogenic control is an important advance in the control of rodent infestation. 1

b t f the present invention tofprovide new and unsaturated linkages in Rings A, B,

This invention is for improvements 'in or relating to or magnesium including the mono-Grignard derivatives, and subsequently regenerating the desired derivative from diyne in liquid ammonia.

3,164,617 Patented Jan. 1965 17a-butadiynyl steroids having, apart from substiuterits C and D, the general formula According to the present invention, thereis provided. a process for the preparation of 17u-butadiynyl steroids, having, apart from substituents and unsaturated linkages in Rings A, B, C and D, the general Formula. I, which process comprises reacting the corresponding 17 0x0- steroid with a derivative of diacetylene in which one of the atoms of hydrogen has been replaced by an equivalent of a metal such as lithium, sodium, potassium, calcium the complex so formed. Monosodio-butadiyn e (Armitage, Jones and Whiting, J. Chem. Soc., 1952, 1993) is the preferrexl reagent.

Monosodio-butadiyne is conveniently prepared by treating 1,4-dichloro-but-2-yne (Reppe et al., Annalen, 1955, 596, 78) in a refluxing solution of liquid ammonia with 3 molecular proportions of sodamide preferably with exclusion of moisture; Somewhat less than one molecular proportion of the l7-oxo-steroidal material is preferably employed and if desired may be added in anhydrous solution in a non-hydroxylic organic solvent such as tetrahydrofuran to the prepared solution of monosodio-buta- After addition is complete, the mixture .is stirred, under reflux, e.g., for up to 2 hours, and theproduct is then liberated from the organometallic complex by methods of prior art applicable to reaction of this type, such for example, as adding" solid ammonium chloride, allowing the ammonia to evaporate and treating the residue with water. The product is purified by careful recrystallization.

As is well-known to those skilled in the art, aliphatic derivatives of diacetylene are frequently of low stability (see Armitage, Jones and Whiting, J. Chem. Soc.,' 1952,

I 1993). We have made the surprising discovery that the product of the present invention are, in general, stable at room temperature in the atmosphere and in presence of diifuse daylight. An attempt to detonate 17abutadiynyl-androst-5-en-3/3,17,8-diol was not successful,

and a sample of the same substance, heated at 100 C. in

the atmosphere for 24 hours showed no signs of decomposition.

We have found, howeven'that the melting point is not, in general, a satisfactory criterion of the purity or identity of the compounds of the present invention. For example,

17a-butadiynyl-androst-5-en-1718-01 fuses with decomposi tion at approximately 135 C., while 17a-butadiynylandrost-5-en-3;9,17,Bdiol decomposes without melting at approximately 215 C. In many cases, a melting point 3 or temperature of decomposition is ill-defined, and its 3v of substituents and unsaturated linkages in Rings A, B, C and D. Thus, the process of the invention may be applied to steroids containing unsaturated linkages at A ,A ,A ,A ,A ,A ,A and A and tocombinations of unsaturated linkages such, for example, as at A and A In addition, the process may be applied to steroids containing 3 or more unsaturated linkages, together forming an aromatic system which may be substituted by halogen if desired. Hydroxyl groups do not interfere with the process of the invention, in particular, hydroxyl groups at positions 2, 3, 4, 5, 6 and 11. Hydroxyl groups may, however, sometimes be advantageously protected by prior conversion .into tetrahydropyranyl derivatives and subsequently regenerated. Acyl-ated hydroxyl groups may be hydrolysed during the course of the reaction with the diacetylide, and may require subsequent regeneration. A-lkyl, alkenyl and alkynyl groups containing up to five carbon atoms such, forexarnple, as methyl, vinyl and propynyl groups, and in particular, methyl groups at C C C and C do not interfere with the process of the invention.

.Oxogigroups. for example at C C or Cgrequire protection bygketal, thioketal, enarnine or enol ether formation and subsequent regeneration. The l7a-butadiynyl-17p hydroxy derivatives obtained from the 3-enol ethers of 3,17-dioxo-A -steroid-s may also be of value in their own right on account of their biological properties and in particular their claud-ogenic properties. Sterically hindered oxo-groups, such as at C when an unsaturated linkage is present in the molecule at C or C will, in general, prove unreactive. 5,6- epoxidev groups do not interfere with the process of the invention.

The process of the invention is particularly applicable to derivatives of androst-ane represented as general Formulae II, III, IV and V, and of oestrane represented by general Formulae VI, VII and VIII Me Me 0 I I R (\I R I i; 1'1 R R! R! (II) (III) Me Me O O II II R i R I I Me 0 Me Me Me II l I I i R! R R R (V (V I v f1 YO- i l v (VIII) where is OX (whereX: is lower alkyl, cyclic alkyl or benzyl), H or alkyl; v

R is Me or H R is I I l CHOH, OHOAcyl, '0 CHOY removed (cf; Herzog, Ievnik, Tully and Hershberg,

J. Amer; Chem. Soc., 1953, 75, 4425.). The resulting ketal is then treated with the diacetylide derivative. The ketal group is removed by hydrolysis usually in the presence of an acid catalyst yielding the 17a-butadiynyl-Uri-hydroxyandrost-4-en-3-one derivative.

Alternatively, a 175-hydroxy-3-oxo A -steroid may be converted into a derivative such as a 3-ketal or 3-enol. etherand the secondary hydroxylic group at C converted into a 17-oxo group by oxidation with, for example,

' chromic acid/ pyridine. The 17-oxo-3-ketalised or enolised steroid thereby obtained may then be condensed with the diacetylide derivative as described above.

A procedure applicable to and particularly convenient for 3,17-dioxo-A -steroids is to convert them into the 3-enol ether-17-ones by methods of prior art and to condense these materials with the .acetylide, subsequently regenerating the 3-oxo-A -system by treatment with H+ ions.

In the preparations of the 3-oxo-A -derivatives of 17abutadiynyl-l9-nor-androstane, thereadily available oestra- 2,5(10)-dien-3-ol-17-one-3-methy1 other may be treated with the diacetylide according to the process of the invention. Warming with a mineral acid then regenerates the 3-oxo-4-ene grouping. The 3-enol ethers of a 19-norandrost-4-ene-3,17-dione may also be employed.

In certain cases it may be advantageous to reduce an oxo group (other than at C to hydroxyl and subsequently to regenerate it by oxidation.

The present invention provides veterinary preparations of the new l7a-butadiynyl-l7/3-hydroxy steroidal derivatives. Oral forms of administration are preferred to injectable preparations. In particular the products of the invention may be administered as tablets or as food additives. v The process of the invention may be applied to give the following compounds:

l7a-butadiyny1-oestra-1 ,3,5 10) -trien-3 17/3-diol-3-di.-

ethyl-aminoethyl ether 17a-butadiynyl-l-methyl-oestra-l ,3,5 ()trien-3, 17 p diol 17a-butadiynyl 4-methyl-oestra-1,3 ,5 10) -trien-3, 17 B diol 1 1 1 17u-butadiynyl-6fi-methyl-oestra-1,3,5 10) -tn'en-3, 17pdiol 1 1 17a-butadi ynyl-1,2-dimethy1-oestra-1.3 ,5 10 -trien 3 ,175- 1 diol 17a-butadiyny1-1,6a-dimethyl-oestra-1,3,5(10)-trien- 3,17,8-dio1 I 17a-butadiynyl-1,6,B-dimethyl-oestra-1,3,5 (10)-trien- 3 ,17;8-dio1 I 17a-butadiyny1-1,2-dimethyl-oestra-1,3,5 (10) ,6-tetraen- 3,17B-diol 17a-butadiynyl-1,6-dimethy1-oestra-1,3 ,5 (10),6-tetraen- 3, 17B-dio1 17a-butadiynyl-4-methyl-oestra-1,3,5 (10)-trien-1,l7-

diol 17a-butadiynyl-4,6u-dimethyl-oestra 1,3,5 (10)-trien- I 1,17,8-dio1 I 1 1 V 1 l7a-butadiynyl-oestra-1,3,5 (10)-trien-17B-ol 17a-butadiynyl-l-methyl-oestra-1,3,5 (10)-trien-1718-ol 1'7 u-butadiynyl-4-methyl-oestra-1,3,5 (10)-trien-17fl-o1 l7oc-butadiynyl-l,4-dimethyl-oestra-1,3,5 10) -trien-1 713- 01 1 7a-butadiyr1y1-2,4-dimethyl-oestra-1,3,5 l0) -trien-17[3- 17oc-butadiyny1-2-ch1oro-4-methyl-oestra-1,3 ,5 10) trien- 2 17a-butadiynyl-3-methoxy-oestra-2,5 10) -dien-17B-ol 17a-butadiynyl-3-ethoxy-l9-nor-andrqsta-3,5-dien 17,3-

ol 17a-butadiynyl-6-hydroxymethyl 3-methoxy:19-nor- 'androsta-3,5-dien-17 3-ol 1 f V q 17 a-butadiynyl-l9-nor-androst-4-en-17 fl-olii dne' L j 171 -butadiynyl-oestra-5 (1 0).-en-1718-ol 3-one 17u-butadiynyl-3-methoxy+6-rnethy1-19-nor-androst- 17oz-butadiynyl-6a1-methy1-19-nor-androst 4 en-17,3-01- i Following is a description by way ofexample of methods of carrying the invention into effect.

- to evaporate.

6 EXAMPLE 1 1 7 a-Buta diynyl -A ndfosi-S -En-3 5,1 7 3-Di0i Me. i

"CEO-CECE Sodium wire (3.45 g.) and ferric nit-rate (0.05 g.) were added to liquid ammonia (200 ml.) and the mix- I I H ture was stirred under reflux until the blue colour dis appeared, 1,4-dichloro-but-2-yne (6.15 g.) was added dropwise, and after a further five minutes, a solution of dehydro-epi-androsterone (14.1 g.) in anhydrous tetrahydrofuran (100 ml.) was added. The mixture was stirred under reflux for 1 /2 hours, solid ammonium chloride (6 g.) was addedyand the ammonia was allowed The residue was extracted with ether and the ethereal solution was washed with water, dried over sodium sulphate, treated with charcoal, and evaporated at reduced pressure. The solid residue was purified from methanol, yielding 17u-butadiynyl-androst-5-en-3p-diol, [a] =-17 0 (0., 0.742 in dioxan A.R.),

mm 229.5 mp. (e 314), 241 mp (6 338.5), 254-2545 mp. (e 213) 'y if 3585, 3366, 3156,' 2219, 2139, 1672, 1269, 1249,

1170, 1137, 1082, 1053, 1024, 954, 813, 739 and 725 GEL-1 EXAMPLE 2 V 17a-Butadiynyl-3-Meth0xy-Oestra-1,3,5 (10)-Trien- A solution of oestrone 3 methyl ether (13.5 g.) in anhydrous tetrahydrofuran .(300 ml.) was added to alsolution prepared from liquid ammonia (200 ml.), sodium (3.45 g.).ferric nitrate (0.05 g.) and 1,4-dichlorobut-2-yne (6.15 g.) by the method of Example 1. The mixture was stirred under reflux for 1 hour and treated with solid ammonium chloride (6 g.), and the ammonia was allowed to evaporate. Ether extraction, the ethereal solution being washed, dried, treated with charcoal, and evaporated at reduced pressure, yielded a gum which, purified from aqueous methanol and from ether/petroleum ether gave crystalline l7a-butadiynyl-3-methoxy- EtOH pure) xfifzms m (5 1,930 and 287.5 m. (6 1,830); 1539 256 111,1:(6 528); 9, 9; 3609, 3310, 2229, 2059, 1611,

. 7" EXAMPLE'3 1761-13utadZynyZEAnd Ost-S En-Z7, 101.

A solution of androst-S-en-one (4.6 g.) (U.S. Patent 2,397,424) in anhydrous tetrahydrofuran (35 ml.) was added to a solution prepared from liquid ammonia (100 ml.), sodium (1.17 g), ferric nitrate (0.02 g.) and 1,4-dichloro-but-Z-yne (2.08 g.) by the method of Example 1. The mixture was stirred under reflux for 2 hours and treated with solid ammonium chloride (2 g.),andthe am monia was allowed to evaporate. Ether extraction, the ethereal solution being washed, dried, and evaporated at reduced pressure, yielded a gum which, purified from aqueous methanol, gave crystalline 17oi-butadiynyl-an drost-5-en-l7fi-ol, '[06]D22=1-85 (c'. 0.568 in dioxan J, V

C914 3607, 3310, 2221, 2057, 1666, 11457, 1436, and

' max.

1382 emf EXAMPLE '4 17a-ButqdiyriyZ-S-Methoxy-Oestra-ZJ(10)-Dien-I7,8-Ol

p --ozo ozon A solution of 3-methoxy-oestra-2,5(10)-dien 17-one (4.77 g.) (C-olton, Nysted, Riegel and Raymond, J. Amer. Chem. Soc., 1957, 79, 1123) in anhydrous tetrahydrofuran (60 ml.) was added to a solution prepared from liquid ammonia (70 ml.), sodium (1.20 g.), ferric nitrate (0.02 g.) and 1,4-dichloro-but-2-yne (2.10 g.) by the method of Example 1. The solution was stirred under reflux for 2 hours and treated with solid ammonium chloride (2. g.) and the ammonia was allowed to evaporate. The residue was extracted with ether, the ethereal solution was washed, dried and evaporated under reduced pressure. The residual gum was purified from methanol containing a drop ofpyridine to give crystalline l7oc-butadiynyl-3- methoxy-oestra-2,5 l-dien-17 ,8-01, [M (approximate ly) +68 .(c., 0.999 in dioxan A ,R.)

,gg}; 3607, 3313, 2226,2 55. 1 93,1666, 1465, 1452, 1305, 1 31 661- 1 EXAMPL 1'7u-Butadiynyl-19-N0r Andr0st-4 En-1 7,,8-0l'-3-0rie 3 I CEO-CECE.

Dilute hydrochloric acid (3 N; 32 was added to a solution of 17u-butadiynyl-3-methoxy-oestra-2,5(10)- dien-17/3-ol (0.80 g.) (see g ml.) and the mixture was warmed at 60 to 65 C. for minutes, cooled-and poured into. water.

- monia was allowed to evaporate.

max.

' and Yu Cheng Liu, J. Org. Chem., 1951, 16, 1610), (14.9

g.) in anhydrous tetrahydrofuran (200 ml.) was added to a solution prepared from liquid ammonia (200 ml.), sodiurn' (3.45 g.), ferric nitrate. (0.05g.) and 1,4-dichl0robut-2 yne (6.15 g'.) by the method described in Example 1. The solution was, stirred under reflux. for 1 hour,

treatedwith solid ammonium chloride (6 g.) and the am- The residue was extracted-With ether, the ethereal solution was washed, dried and evaporated at reduced pressure, and yielded a gum,

' whichwaspurified from'methanol'containing a drop of pyridine to give l7a-butadiynyl-3-ethoxy-androsta-3,5- dim-1 713:01; I

17a-butadiynyl-3-ethoxy-a.udrosta 3,5-dien-1-7/3-o1 (0,50; 2 g.) was dissolved in methanol (20' ml.), dilute hydrochloric acid (4 N; 10 drops). was added, and the mixture was allowed't'o stand for l ho'ur at room temperature and then poured into water. The precipitate was collected,

washed and: dried. Purificationfrom aqueous. methanol 17u-butadiynyl-androst-4-en-17p-ol-3-one [a] 7 EXAMPLE 7 V i 1 7u-B utadiynybd -M ethyl-AndrosZ-S -En-3 {3,1 7,9-Di0l i :l---ozo. ozorr extraction, the ethereal solution was washed ,*dried', treated Example 4) in'methanol (48 The 'precipit-ate v was collected, washed, dried andpurified by recrystallisation from jrnethanol, yielding 1 7or-but adiynyl-19-nor anwith charcoal and stripped under reduced pressure togive butadiynyl- 6-methyhandrost-5-en-313,17B-dio1 A solution of 3-ethoxy-19-nor-androsta-3,5-dien-17-one (Djerassi, Miramontes, Rosenkranz, Sondheimer, J. Amer. Chem. Soc., 1954, 76, 4092) (5.5 g.) in anhydrous tetrahydrofuran (75 ml.) was added to a solution prepared from liquid ammonia (100 ml), sodium (1.38 g.), ferric nitrate (0.02 g.) and l,4-dichlorobut-2yne (2.46 g.) by the method of Example 1. The solution was stirred under reflux for 2 hours, and treated with solid ammonium chloride (3 g.), and the ammonia was allowed to evaporate. The product, isolated as in Example 7, was crystallised from methanol containing a drop of pyridine, aflording 17a-butadiynyl 3 ethoxy-19-nor androsta-3,5-dien-1718- 01, a 242 m (e 18,850) l I max.

EXAMPLE 9 i OH a residue which was purified from methanol yielding 170;;

p A solution of 3-methoxy-6-methyl-l9-nor-androsta-3,5 dien-l7-one (4.84 g.) (Belgian Patent No. 606,935).in anhydrous tetrahydrofuran ml.) was added to a solu-' tion prepared from liquid ammonia ml.),'sodium (1.21 g.), ferric nitrate (0.01 g.) 'and l,4-dichloro-but-. 2- yne (2.16 g.) by the method of Example 1. The solution was stirred under reflux for 2 hours, and treated with solid ammonium chloride (2.5 g.) and the ammonia-was allowed to evaporate. Following ether extraction, the ethereal solution was Washed, dried, treated with charcoal and stripped to give a gum, which was purified from methanol containing a drop of pyridine, yielding 17 butadiynyl-3-methoxy-6=methyl 19 nor androsta-3,5-' dien-17/8-o1, Amax, 247 my. (6 19,447). v

1 0 EXAMPLE 10 17 q-Butadiynyl-Oestra-S (1 0 -En-J 7 ,B-0l-3-One A- solution of anhydrousloxalic acid (0.64 g.) in water ml.) was addedto a sqlutionfof l7a-butadiynyl-3- methoxyoestra-Lfl10) dier :l7/3 0l (0.83 g. (Example 4). in: methanol ,(200 ml.) and 'the mixture was allowed to standat room'temper altur'e for 1 hour. Ether (400 ml.) was added. I The mixturewasshaken with aqueous sodium bicarbonate solution, and then with water, dried and stripped under reduced" pressure] Purification from methanol yielded 3-one, 1 1

l7abutadiynyl-oestra-5(10)-en-17,B-ok

p figs 3005,3311, 2 22s, 2057, 1723 01115- 1 v V EXAMPLE" 1-1 17d-Bitmdiyhyl-6a-Meihyl-Androst-4-En-1713-Ol-3-0ne "CEO-CECE one (Belgian Patent No. 606,935) (14.3 g. in anhydrous.

tetrahydrofunan (200 m1.) was added to a solution pre-. pared from; liquid ammonia (250 ml.),sodium (3.45 g.-), ferric nitrate; (0.05 g.) and 1,4-dichloro-but-2-yne (6.15 g.) ;by, the-method of Example 1. The solution was stirred under reflux for l hour and treated with solid ammonium chloride (6 g.) and the ammonia was allowed to evaporate. Followingjether extraction, the ethereal solution, was washed, dried, treated with charcoal and evaporated at reduced pressure, yielding a residue of 170:- hutadiynyl-3-ethoxy-6-methyl-androsta-3,S-dien 176 01. A portion was purified from methanol containing a trace of pyridine. The remainder, .without further purification was dissolved in methanol (600 ml). Dilute hydrochloric acid (3 N; 300 ml.) was added, and the mixture was maintained at 60 C. for 15 minutes, cooled, and poured onto ice. The precipitate was collected, washed with water, dried, and purified by recrystallisation from aqueous methanol yielding 17a-butadiynyl-6a-tmethylandrost-4-en-l7fi-ol-3-one,

,ggg 3 06,3311, 2225,2055, 16.76, 16.10 emf (0.05 g.) and 1,4-diohloto but-2-yne (6.15 g.) and the EXAMPLE 12 (1.75 g liquid ammonia (100 ml.), ferric nitrate 0.05 17a ButtidiyiiyI4-MethyZ-Andr0l9t 4 Erz-17fl Ol 3 0ne and (3 accordmg to the process of Example 1. The product obtained was iso 5 to give 17a-butadiynyl-oestra1,3,5-(10)-trien-17,6 ol as. needles, MP. 100 to 102? C., [-a] 35.2 (0., 1.0 in chloroform), iggg 241.5 ma (6 377), 255.3671 and (e 426), 266.5

my (6 460), 274 m (e 417), 7,9 3604, 3311, 2230 and 2061, cmr

' EXAMPLE The 3 ethy1ene glycol ketal of 4; math Y1; an dro st I5. l7a-Butadlynyl-4-Methyloestra-13,5(10)-Trzen-171 -0l 17-dione (Belgian Patent No. 606,935) (14.8 g.) in anhydrous tet-rahydrofuran (200 ml.) was added to a solution. prepared by the method of Example 1 from Me liquid ammonia (200 ml.), sodium (3.45 g.), ferric nit-rate R G 0 C E EOH mixture was stirred under refluxfor 1 hour. Solid am'-- r'noniuin chloride (6. g.) was added, and the ammonia was allowed to evaporate. After etherextraction, the I ethereal solution was washed, dried, and evaporated at reduced pressure, yielding a residue "of the 3=ethylene 2 glycol ketal *of' 17aabutadiynyl-4-imethyhandrost=4-en- 17,8 ol-3-o'ne. Without being purified, this was dissolved in methanol (500 ml.). Dilute hydorchloric acid (4 N; 50 ml.): was added, and themixtu-re was allowed to I stand for 1 hour at room temperature'and then poured O Mg gif gig ggg g gf iz gfi gi g: g i gg gj into water. The precipitate was collected, washed, dried 809 37,02) in dry tetrahydrofmani (100, ml) was treated and purified from aqueous methanol yielding 17owbuwith the-sodium saltrofibutadiynre [prepared from Sodium 1.75 g.), liquid ammonia 100 ml.),.ferric nitrate 0.05 235,? 3502,3216, 2220,2139,1697f1642 cmr g.) and 1,4-dich1oro-but-2-yne (3 g.)'] according to the process of Example 1. The product was crystallised from EXAMPLE 13 aqueous methanol to give l7a-bIitadiynyIA-methyloestra- 17ot-BUtadiynyl-Andr0sta-3,5-Dien-1713-0! f B- as P With Me q I decomposltion, I i q oo1 cs 7 v u: EECECAEECH v 40 'y f 3600, 3305, 2225, 2055, 1590, 780, 745

EXAMPLE 16 e e 17a-Butadiynyl0estra-1,3,5 (10)-Trien-3,1713-Di0l I Me . A solution of iandrosta-3,5 -dienl7 one (2.5 g) CEC GECH (Rosenkranz, Kaufman and Rome, J. Amer, Chem. Soc, 1949, 71, 3689") in tetrahydroiiunan (50 ml.) was added to a solution prepared from liquid ammonia (75 ml.), i odiuzm "(O/69g), ferric nitrate (0.01 g.) and 1,4-dichloro H but-Z-yne (1.23 g.) by the method of Example 1. The mixture was stirred under reflux for 2 hours and treated with solid ammonium chloride (2 g and the ammonia was a lowed to evaporate. The product, isolated with ether, was purified from aqueous methanolto give 170i- 3 (tetrahydropyranyl 2 L oxy)oestra-1,3,5(10)-trien- 17-one (10 g.) (prepared as in Belgian Patent No. 606,- 935) in dry tetrahydrofuran (200 ml.) was treated with butadiynyhandrosta iifi dim-1718 01,

EXAMPLE 14 V V the sodium salt of butadiyne [prepared from sodium (3.6

; p I g.), liquid ammonia (200 ml.), ferric nitrate (0.1 and i B' 1,4-dichloro-but-2-yne (6.4 g.)] according to the g ocess Me of Example 1. p q

. :11 g Y The product was kept at room temperature for 6 hours O-Q Q in methanol (200 ml.) containing toluene-p-sulphonic 1 i acid (1 g.). The solution Was poured into water, the

. 1 1 1 j 1 1 I steroidal material was extracted into ether, the extract was washed with dilute aqueous sodium bicarbonate and water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. crystallisation I of the residue from benzene gave 17ot-butadiynyloestra- 1,3,5(10)-triene-3,l7,8-diol, MP. 134 to 137 C. with Oestra-1,3,5(10)-tr1en-17-one (5 g.) (U.S. Eatent No. decomposition 2,947,763) in dry tetra-hydrofuran 50 ml.) was treated with the sodium s l of butfidiyne [Prepared from sodium 3261 2227 21001 1615 715521 14961 'l ated with ether and crystallisedv from aqueousacetone 13 1 EXAMPLE 17 17u-Butqdiynyl-19-Nor-Androst 4-En-1 75-01 Me i V a 1 "CEO-CECE 335 3602, 3305, 2227, 2057, 1665 emr EXAMPLE 18 1 7u-Butadiynyl-5a-A ndrostan-I 75-0l-3-One O5CC CH Me a A solution of 3-methoxy-5a-androst-2-en-17-one (12.0 g.) (Belgian Patent No. 606,935, Example in anhydrous tetrahydrofuran (300 ml.) was added to a solution prepared from liquid ammonia (300 ml.), sodium (3.45 g.), ferric nitrate (0.05 g.) and 1,4-dichloro-but-2-yne (6.15 g.) by the method of Example 1. The solution was stirred under reflux for 2 hours and treated with solid ammonium chloride (6 g.), and the ammonia was allowed to evaporate. The residue was extracted with ether, and the ethereal solution was washed, dried, treated with charcoal and stripped. The residual gum was dissolved in methanol containing 1% of concentrated hydrochloric acid, and the solution was heated under reflux for 10 minutes, cooled and diluted with water. 1 The precipitate was collected, and purified from aqueous methanol, yielded 17a-butadiynyl-5a-androstan-l7fl-ol-3-one,

EXAMPLE 19 17a-Butadiynyl-6a-Methyl-5a-A ndrostan-I 7fl-Ol-3-One -CEC- CECE CH3 A solution of 3,3-dimethoxy-6m-methyl-5rat-androstan- 17-one (1.26 g.) (Belgian Patent No. 606,935) (Example one,

14 33) in anhydrous tetrahydrofuran (ml) wasadded to a solution prepared from liquid ammonia (100 ml.)

sodium (0.35 g.), ferric nitrate (0.0lg.) and 1,4-dichlorobut-Z-yne (0.62 g.) by the method of Example 1, The

.1 solution was stirred under reflux for 2 hours and treated with solid ammonium chloride (1.5 g.), and the ammonia was allowed to evaporate. The residue was extracted with ether, and the ethereal solution was washed, dried, treated with charcoal, and stripped. The residual gum was dissolved in- 1% methanolic hydrogen chloride and the solution was heated under reflux for 10 minutes, cooled and diluted with water. Purification ,of the precipitate from methanol containing a few drops of water yielded 170c'- butadiynl-6a-methyl-5 a-androstan-l7fi-ol-3- EX MPLE"20 i j e 17a-Butadiynyl-4a Methyl-5a-Andr0stan-1 7fl-ol-3-0ne A solution of 3-methoxy-4m methyl-5a-androst-2-en-17- one (3.0 g.) (Belgian Patent No. 606,935, Example 21) in anhydrous tetrahydrofuran (100 ml.) wasadded to a solution prepared from liquid ammonia ml.), sodium (0.69 g.) ferric nitrate (0.02 .g.) and 1,4-dichlorobut-2-yne (1.23 g.) by the method of Example 1. The solution was stirred under reflux for 2 hours and treated with solid ammonium chloride (2 g.) and the ammonia was allowed to evaporate. The residue was extracted with ether, and the ethereal solution was washed, dried, treated with charcoal and stripped. The residue was heated under reflux for 10 minutes with 1% solution of hydrogen chloride in methanol, and the resulting solution was cooled and diluted with water. The precipitate was purified from aqueous methanol, yielding 17a-butadiynyl-4a-methyl-5a-androstan-l7 8-ol-3-one,

We claim:

I. A 17a-butadiynyl-17,B-hydroxy steroid compound selected from the group consisting of '17a-butadiynl-17fihydroxy steroid compounds of the androstane and oestrane series.

2. a butadiynyl androst 5 en 3,8, 1718 diol.

3. 17oz butadiynyl 3 methoxy oestra 1,3,5(10) trien l 7 3-01.

4. 17oz butadiynyl androst 5 en 17B ol.

5. 17a butadiynyl 3 methoxy oestra 2,5 (10) dien-17601.

6. 17a butadiynyl 19 nor androst 4 en 17 3 ol-3-one.

8. 17oz butadiynyl androst 4 en 17 3 ol 3 one.

9. 17a butadiynyl 6 methyl androst 5 en 3 3, 17 3, diol.

10. 170: butadiynyl 3 ethoxy 19 nor androsta 3,5-dien-17fl-ol.

11. 1704 butadiynyl 3 methoxy 6 methyl 19 nor-androsta-3,5-dien-17B-ol.

12. 170: butadiynyl oestra 5(10) en 17B o1 3-one.

butadiynyl 3 ethoxy androsta 3,5 dien 13. 17a butadiynyl 3 -ethoXy-- 6 -methyl androsta- 15. 17a butad-iynyl-A methyl andfrost 4 err- 17 ,6-ol-3-one. I

1.6. 17 butadiynyl -v androsta 3,5 dien 17s o1.

20. 17cc -butadiynyl 19 nor androst 4 -"en 1-75 o1.

21. 17oz but-adiynyl 5o; androstan- 17B ol 3 one 5 l a I 22. 17c; butadiynyl 60c -Imethyl'- 50c androstan 1 7/3-ol-3-one.

' t 23; I764 butadiynyl 40 methyl 5a -randrostan 1'7/3-ol-3-one.

24. A process for the preparation of 17a-butadiynyl- 17 3-hydroxy steroids of the androstane andoestrane series which process comp-rises reacting the corresponding 17- oxo-steroid with a derivative of diacetylene in which one methyl andros t 4 en of the atoms of hydrogen has been replaced by an equivalent of a metal selected from the group consisting of lithium, sodium, potassium, calciumand magnesium,

and treating the o'rgano-metallic' complex so formed with 1 ammonium chloride to liberatesaid l7a-butadiynyl-17flhydroxy steroid. i

25. In a-process for the preparation of 17a-butadiynyl- 17 8 hydroxy steroids of the androstane and oestrane series, the step comprising reacting the corresponding l7-oXo-steroid with a derivative of diacetylene in which one of the atoms of hydrogen has been replaced by an equivalent of a metal selected from the group consisting of lithium, sodium, potassium, calcium and magnesium.

26. A process as claimed in cliam 25 wherein the 17- oX'o-ster-oid is reacted with monosodio butadiyne. 27. A process as claimed in claim26 wherein the mon-' osodio-butadiyne is prepared by treating 1,4-dich1oro-but- 2-'yne in a refluxing solution of liquid ammonia with three molecular proportions of sodamide. V

28. A process as claimed in claim 25 wherein the 17 oxo steroidal starting material is dissolved in tetrahydro furan.

No references cited. 

1. A 17A - BUTADIYNYL-17B-HYDROXY STEROID COMPOUND SELECTED FROM THE GROUP CONSISTING OF 17A-BUTADIYNL-17BHYDROXY STEROID COMPOUNDS OF THE ANDROSTANE AND OESTRANE SERIES.
 8. 17A - BUTADIYNYL - ANDROST - 4 - EN - 17B - OL - 3 - ONE. 